PROGRAM FACULTY. Washington D.C. July 16th, Anne L. Leddy, MD, FACE. Felice Caldarella, MD, FACE, FACP, CDE. Endocrinologist

Transcription

1 July 1th, 215 Wshington D.C. PROGRAM FACULTY Felice Cldrell, MD, FACE, FACP, CDE Anne L. Leddy, MD, FACE Endocrinologist Consulting Endocrinologist Center for Endocrine Helth Clinton, New Jersey. Gloucester Mthews Cre Clinic Gloucester, Virgini

2 Session 9: Combining GLP-1 Receptor Agonists with Bsl : Relizing the Potentil in Type 2 Dibetes Lerning Objectives 1. Implement ADA recommendtions for A1C, fsting plsm glucose, nd post-prndil glucose trgets in the mngement of ptients with type 2 dibetes. 2. Assess the clinicl profiles of GLP-1 receptor gonists nd the dvntges nd disdvntges of prndil insulin 3. Describe the clinicl rtionle nd expected benefits of using ntidibetic therpies with complementry mechnisms of ction in the tretment of ptients with type 2 dibetes. 4. Utilize pproprite strtegies to select nd intensify ntidibetic therpy to chieve PPG control in ptients with type 2 dibetes on bsl insulin Fculty Felice Cldrell, MD, FACE, FACP, CDE Endocrinologist Center for Endocrine Helth Clinton, New Jersey Dr Cldrell is grdute of New York University nd received his medicl degree from S.U.N.Y. Upstte Medicl University. He completed his residency t Brown University in Rhode Islnd. Dr Cldrell went on to receive subspecilty trining in Endocrinology, Dibetes nd Metbolism t UMDNJ. He is bord certified in Endocrinology, Dibetes nd Metbolism. He is Fellow of the Americn College of Endocrinology nd Fellow of the Americn College of Physicins. He is lso Certified Dibetes Eductor. Dr Cldrell ws recognized s New Jersey Top Doc for 211. Dr Cldrell supervises the mediclly supervised weight loss progrm t the Center for Advnced Weight Loss. Anne L. Leddy MD, FACE Consulting Endocrinologistst Gloucester Mthews Cre Clinic Gloucester, Virgini Dr Leddy is grdute of the Johns Hopkins University School of Medicine in Bltimore Mrylnd were she returned for her Endocrine Fellowship. She remined on the clinicl fculty t Hopkins for severl yers. In 19 she moved to Newport News Virgini where she prcticed generl endocrinology with focus on dibetes, thyroid disese nd metbolic bone disese. Since 213, she hs directed dibetes cre t the non- profit Gloucester Mthews Cre Clinic which serves the working poor in two rurl Virgini counties. Dr Leddy is member of the Americn Assocition of Clinicl Endocrinologists nd hs been member of the orgniztion s ntionl Bord of Directors since 211. Fculty Finncil Disclosure Sttements The presenting fculty reported the following: Dr Cldrell hs served on the Speker's Bureu for NoroNordisk, Slix, nd Tked. Dr Anne Leddy hs nothing to disclose. Session 9

3 Eduction Prtner Finncil Disclosure Sttement The content collbortors t Horizon CME hve no reltionships to disclose. Acronym List Acronym ASP BG DET DPP-4I FPG GIP GLAR GLP-1 RA GLU MET Definition insulin sprt blood glucose insulin detemir dipeptidyl peptidse-4 inhibitor fsting plsm glucose glucose-dependent insulinotropic polypeptide insulin glrgine glucgon-like peptide-1 receptor gonist insulin glulisine metformin NPH NSHE OAD OHA PG PPG SGLT-2 SMBG SU T1DM T2D/T2DM TZD neutrl protmine Hgedorn nonsevere hypoglycemic events orl ntidibetic drugs orl hypoglycemic gents plsm glucose postprndil glucose sodium glucose trnsporter-2 self-monitoring of blood glucose sulfonylure type 1 dibetes type 2 dibetes thizoldinedione Suggested Reding List Rodbrd HW, Blonde L, Brithwite SS, et l. Americn Assocition of Clinicl Endocrinologists medicl guidelines for clinicl prctice for the mngement of dibetes mellitus. Endocr Prct. 27;13 Suppl 1:1-. Americn Dibetes Assocition. 7. Approches to Glycemic Tretment. Dibetes Cre. 215;3(Supplement 1):S41-S4. Blen R, Hensley IE, Miller S, Brnett AH. Combintion therpy with GLP-1 receptor gonists nd bsl insulin: systemtic review of the literture. Dibetes Obes Metb. 213;15(): Giuglino D, Miorino MI, Bellstell G, Chiodini P, Esposito K. Tretment regimens with insulin nlogues nd hemoglobin A1c trget of <7% in type 2 dibetes: systemtic review. Dibetes Res Clin Prct. 211;92(1):1-1. Monnier L, Colette C, Dunseth GJ, Owens DR. The loss of postprndil glycemic control precedes stepwise deteriortion of fsting with worsening dibetes. Dibetes Cre. 27;3(2): Riddle M, Umpierrez G, DiGenio A, Zhou R, Rosenstock J. Contributions of bsl nd postprndil hyperglycemi over wide rnge of A1C levels before nd fter tretment intensifiction in type 2 dibetes. Dibetes Cre. 211;34(12): Turner RC, Cull CA, Frighi V, Holmn RR, for the UK Prospective Dibetes Study (UKPDS) Group. Glycemic control with diet, sulfonylure, metformin, or insulin in ptients with type 2 dibetes mellitus: progressive requirement for multiple therpies (UKPDS 49). JAMA:1999;21(21): Rcch D, Hk TJ, Huet D, et l. Comprison of stepwise ddition of prndil insulin to bsl-bolus regimen when bsl insulin is insufficient for glycemic control in type 2 dibetes: results of the OSIRIS study. Dibetes Metb. 212;3(): Session 9

4 11: m 12:15 pm Combining GLP-1 Receptor Agonists with Bsl : Relizing the Potentil in Type 2 Dibetes SPEAKERS Felice Cldrell, MD, FACE, FACP, CDE Anne L. Leddy, MD, FACE Presenter Disclosure Informtion The following reltionships exist relted to this presenttion: Felice Cldrell, MD, FACE, FACP, CDE: Speker's Bureu for Novo Nordisk, Slix, nd Tked. Anne L. Leddy, MD, FACE: No finncil reltionships to disclose. Off-Lbel/Investigtionl Discussion In ccordnce with pmicme policy, fculty hve been sked to disclose discussion of unlbeled or unpproved use(s) of drugs or devices during the course of their presenttions. Combining GLP-1 Receptor Agonists with Bsl : Relizing the Potentil in Type 2 Dibetes Felice Cldrell, MD, FACE, CDE, FACP Endocrinologist Center for Endocrine Helth Clinton, NJ Anne L. Leddy, MD, FACE Consulting Endocrinologist Gloucester Mthews Cre Clinic Gloucester, Virgini Objectives Implement ADA recommendtions for A1C, fsting plsm glucose, nd post-prndil glucose trgets in the mngement of ptients with type 2 dibetes Assess the clinicl profiles of GLP-1 receptor gonists nd the dvntges nd disdvntges of prndil insulin Describe the clinicl rtionle nd expected benefits of using ntidibetic therpies with complementry mechnisms of ction in the tretment of ptients with type 2 dibetes Utilize pproprite strtegies to select nd intensify ntidibetic therpy to chieve PPG control in ptients with type 2 dibetes on bsl insulin Combining GLP-1 Receptor Agonists with Bsl : Relizing the Potentil in Type 2 Dibetes Felice Cldrell, MD, FACE, CDE, FACP Endocrinologist Center for Endocrine Helth Clinton, NJ Normoglycemi nd Recommended Glycemic Trgets in T2DM Glucose Control Helthy Individuls 1-3 A1C, % <. Preprndil PG, mg/dl Pek postprndil PG, mg/dl ADA AACE Individulized Trget <. <7. most pts <.5 helthy pts Individulized Trget 7.-. <.5 most pts <1-13 <11 <14 <1 <14 b Pek postprndil cpillry plsm glucose; b 2-hour postprndil glucose concentrtion; Ptients with known CVD or multiple co-morbidities. PG = plsm glucose; ADA = Americn Dibetes Assocition. 1. ADA. Clinicl Prctice Recommendtions 215. Dibetes Cre 215;3(Suppl. 1):S33 S4. 2.ADA. Stndrds of Medicl Cre in Dibetes-214. Dibetes Cre. 214;37(1 Suppl):S14-S. 3. ADA. Dibetes Cre. 21;24: Grber AJ, et l. Endocr Prct. 213;19: Hndelsmn Y, et l. Endocr Prct. 211;17(Suppl 2):1-53.

5 When to Consider in Type 2 Dibetes Ptients with symptomtic hyperglycemi When combintion orl/injectble gents become indequte (A1C >7.-7.5%) High FPG or high PPG Uncceptble side effects of other gents Specil circumstnces (e.g., steroids, infection, pregnncy), heptic nd renl disese Ptient with hyperglycemi in the hospitl Severely uncontrolled dibetes FPG = fsting plsm glucose; PPG = postprndil glucose. Defined s fsting glucose >25 mg/dl, rndom glucose > 3 mg/dl, A1C >1%, ketonuri, or symptomtic (polyuri, polydipsi, nd weight loss) by ADA 29 Consensus Sttement. After glucose controlled, orl gents cn be dded nd insulin withdrwn if preferred. Nthn DM, et l. Dibetes Cre. 29; volume 32, Inzucchi SE, et l. Dibetes Cre. 212;35(): ADA Dibetes Cre. 214:37(Suppl 1):S14-S. Glycemic Control Declines over Time with Trditionl Monotherpy Ptients (%) with A1c <7% Most ptients on trditionl therpies will require nother gent to mintin long-term glycemic control % 34% 13% 3 yr yr 9 yr 3 yr yr 9 yr Adequtely Controlled nd Treted with Metformin Adequtely Controlled nd Treted with Sulfonylures Overweight drug-nïve ptients. Norml weight nd overweight drug-nïve ptients. Turner RC, et l. JAMA. 1999;21:25 Ptients (%) with A1c <7% % 34% 24% UKPDS: Progressive Deteriortion in Glycemic Control over Time 9 HbA1C Level 1 bet-cell Function Bsl Therpy Concept nd Physiology Medin A1c (%) 7 Conventionl Intensive B-cell Function (%) Time from Rndomiztion (y) Yers from Dignosis UKPDS Group. Lncet. 199;352: Holmn RR. Dibetes Res Clin Prct. 199;4(suppl):S21-S25. Postprndil Hyperglycemi Persists fter Bsl Therpy 14 ptients with bseline A1c 7.5% on diet, orl gents, or insulin. Meltime hyperglycemi persisted fter 3 months of intensive tretment. Phrmcokinetic Profile of Bsl s Glucose (mg/dl) A1c >7% (n=44) A1c 7% (n=12) Plsm Levels Intermedite (NPH insulin) Long ( detemir) Long ( glrgine) Ultr long (U3 glrgine) 12 1 Woerle HJ, et l. Dibetes Res Clin Prct. 27;7: Hours 4: : : 1: 2: 14: 1: 22: : 12: 1: 2: 24: 2: 2: 3:32: 34:3: Time (h) NPH = neutrl protmine Hgedorn Adpted from Hirsh IB. NEJM. 25; 352: Flood TM. J Fm Prct. 27;5(suppl 1):S1-S12. Becker RH, et l. Dibetes Cre. 214;pii:DC_14.

6 A Simple Approch to Strting Bsl Bedtime or morning long-cting insulin OR Bedtime intermedite-cting insulin Dily dose: 1 units or.1-.2 units/kg/dy Check FBG dily Increse dose by 2-4 units every 3 dys until FPG is 7-13 mg/dl Continue regimen nd check A1C every 3 months In the event of hypoglycemi or FPG level <7 mg/dl: Reduce bedtime insulin dose by 4 units, or by 1-2% FPG = fsting plsm glucose Nthn DM, et l. Dibetes Cre. 29;32: ADA. Dibetes Cre. 215;3(suppl 1):S41-S4. Anlogue Bsl Compred to NPH in T2DM Ptients on OADs Ptients (%) with 1 Hypoglycemi Episode No difference in FPG nd A1C control but significntly less nocturnl hypoglycemi with nlogue bsl insulin 2 Bsl Glrgine NPH p<.5 vs. insulin glrgine; hypoglycemi is defined s PG 72 mg/dl. OAD = orl ntidibetic drugs; B = Brekfst; L = Lunch; D = Dinner. Riddle M, et l. Dibetes Cre. 23;2: B L D 1 Time of Dy (hr) HbA1c Effective Dose Titrtion of Consistently Reduces A1C to Trget Tret-to- Trget 1 Clinicl Trils of Anlogue Glrgine LANMET 2 Bseline.71.9 APOLLO 3 Study Endpoint LAPTOP 4 1. Riddle M, et l. Dibetes Cre. 23;2: Yki-Jrvinen H, et l. Dibetologi. 2;49: Bretzel RG, et l. Dibetes. 2;55(Suppl). Abstrct 32-OR. 4. Jnk H, et l. Dibetes Cre. 25;2: Rosenstock J, et l. Dibetes Cre. 2;29: Yki-Jrvinen H, et l. Dibetes Cre. 2; 55. Abstrct 125-OR Triple Therpy 5.. INITIATE Combined Effects of Metformin with Therpy in Type 2 Dibetes Subject (n) Durtion (mo) dose t end (U) A1C t end (%) Weight gin (kg) Yki-Järvinen et l. + Metformin Avilés-Snt et l. + Metformin Strowig et l. + Metformin Wulffelé et l. + Metformin All of the studies compred subjects on insulin versus metformin nd insulin. All found less weight gin, lower insulin dosge, nd mostly comprble A1C control. Ssli A nd Lehy JL. Curr Dib Rep. 23;3: Wht if Bsl Is Not Enough? Glucose Concentrtion (mmol/l) Stepwise Glycemic Deteriortion in T2DM Fsting (nocturnl period) 2 4 Brekfst Morning Period Postprndil (dytime period) Time (h) Dibetes Durtion (yrs) Monnier L, et l. Dibetes Cre. 27;3:23-29.

7 Reltive Contribution of FPG nd PPG to A1C Mtching Tretment to Disese Progression Using Stepwise Approch 1 Fsting glucose Postprndil glucose Bsl Plus: Once-dily bsl insulin glrgine or detemir plus once-dily rpid-cting insulin Bsl Bolus Add Prndil before Ech Mel Contribution (%) 4 2 3% 7% 5% 5% 55% 45% % 4% 7% 3% <7.3% %.5-9.2% % >1.2% Bsl Add Bsl nd Titrte Bsl Plus Add Prndil t Min Mel Lifestyle Chnges plus Metformin (± other gents) n = 5 n = 5 n = 5 n = 5 n = 5 A1C Quintiles Progressive Deteriortion of -cell Function Monnier L, et l. Dibetes Cre. 23;2:1-5. Rcch D, et l. Dibetes Metb Res Rev. 27;23: Poorly controlled on bsl insulin + MET (N=11) Intensifiction: OSIRIS Study Design N=14 Switched to GLAR for A1C months >7.% nd N=197 FPG <12 mg/dl (n=47) N=123 Group 1:GLAR + MET + 3xGLU Group 2: GLAR + MET + 1, 2, or 3xGLU Group 3: GLAR + MET + SU + 1, 2, or 3xGLU Rndomiztion nd 12 Month F/U Orl ntidibetic gents were continued. GLAR = insulin glrgine; GLU = insulin glulisine; MET = metformin; SU = sulfonylure. Rcch D, et l. Dibetes Metb. 212;3(): Men in A1C (%) OSIRIS Study: Chnge in A1C nd Weight Chnge in A1C from Rndomiztion to Endpoint Rndomiztion GLAR = insulin glrgine; GLU = insulin glulisine; MET = metformin; SU = sulfonylure. Rcch D, et l. Dibetes Metb. 212;3(): Weight (kg) Group 1: GLAR + MET + 3xGLU Group 2: GLAR + MET + 1, 2, or 3xGLU Group 3: GLAR + MET + SU + 1,2, or 3xGLU Chnge in Body Weight (kg) 2.3 p= Intensifiction: STEP-WISE Study Design STEP-WISE Study: Chnge in A1C 9..9 Poorly controlled on bsl insulin + 1 to 3 OADs (N=345) Switched to IDet for 12 weeks R SimpleSTEP (N=15) A1c 7.% (n=29) ExtrSTEP b (N=14) IDet + OADs + 1, 2, or 3xIAsp IDet + OADs + 1, 2, or 3 IAsp SU discontinued; SimpleSTEP = sequentil ddition of IAsp to mel(s) perceived by the ptient s being the lrgest of the dy, with titrtions bsed on the premel plsm glucose concentrtion; b ExtrSTEP = sequentil ddition of IAsp to mel(s) with the highest mesured PPG increse, with titrtions bsed on the PPG level. IDet = insulin detemir; IAsp = insulin sprt; SU = sulfonylure; PPG = postprndil glucose. Meneghini L, et l. Endocr Prct. 211;17(5): HbA1c (%) Period 1 Period 2 Period Weeks ExtrSTEP SimpleSTEP b SimpleSTEP = sequentil ddition of IAsp to mel(s) perceived by the ptient s being the lrgest of the dy, with titrtions bsed on the premel plsm glucose concentrtion; b ExtrSTEP = sequentil ddition of IAsp to mel(s) with the highest mesured PPG increse, with titrtions bsed on the PPG level. Meneghini L, et l. Endocr Prct. 211;17(5):

8 Regimens with Anlogues nd A1C <7% in Type 2 Dibetes Ptients Bsl Bolus Regimen: Percent of Ptients with A1C <7% Systemtic review of RCT 4 trils, 5 rms, 3,5 ptients with primry outcome of A1C <7% in ptients with T2DM 12 trils, with 2114 ptients A1c <7% ws chieved in 53.9% Study (first uthor, yer, reference) Hollnder, 2 (44) Hollnder, 2 (44) Bsl Bolus Regimen Proportion of Ptients with HbA1c <7% Bsl insulin (n=17,5): 41.4% Biphsic insulin (n=9,237): 4.5% Hypoglycemic events (men/ptient/3 dys):. ( ) Rosenstock, 2 (4) Bergenstl, 2 (47) Bergenstl, 2 (47) Lnkisch, 2 (49) Prndil insulin (n=1,5): 39.% Bsl-bolus insulin (n=2,114): 53.9% Men weight gin ~2.75 kg Men finl insulin dose:.9 U/kg Lnkisch, 2 (49) Liebl, 29 (5) Riddle, 29 (53) Rskin, 29 (59) Incidence of hypoglycemi rnged from to 4.71 events/ptient/3 dys Weight gin rnged from 1.75 kg for bsl to 3 kg for biphsic insulin. Escltion from bsl to bsl-bolus increses success rte in n dditionl ~12% to 14% of ptients HbA1c <7% is chieved in ~54% of ptients Rskin, 29 (59) Fritsche, 29 (5) Pooled Estimte (95% CI) 53.9% (43.5%-4.%) Giuglino D, et l. Dibetes Res Clin Prct. 211;92(1):1-1. Giuglino D, et l. Dibetes Res Clin Prct. 211;92(1):1-1. Adding Prndil to Bsl Advntges Trets postprndil hyperglycemi Increses success rte in chieving A1c <7% Disdvntges Increses weight gin Increses hypoglycemi risk Less convenient with multiple injections Increses success rte only by n dditionl 12% to 14% Hypoglycemi How Often Does Hypoglycemi Occur in Type 2 Dibetes? Risk of Hypoglycemi Increses s Therpy Intensifies Frequency of NSHE (%) Dily to bout 1/wk NSHE = nonsevere hypoglycemic events. Survey 49 US ptients with T1DM (n=2) nd with T2DM (n=29). Brod M, et l. Vlue Helth. 211;14: /mo to serverl times/mo 4.2 Only few times/y or very rrely Percentge of Ptients Reporting 1 Hypoglycemic Event per Yer (%) Diet Alone For ll therpies, the significnce of differences between levels is p<.1 Metformin SU = sulfonylure. Wright AD, et l. J Dibetes Complict. 2;2: (UKPDS 73) SU 21.2 Bsl Only 32. Bsl + Bolus

9 HRQoL Decrement All Hypoglycemi Negtively Affects Qulity of Life in Ptients with T2DM Alvrez-Guissol 1 (N=179; 3% with events) HRQoL Decrement Mrrett 2 (N=194; 3% with events) Hypoglycemi Severity Hypoglycemi Severity Hypoglycemi is lso ssocited with lower tretment stisfction, poorer dherence, nd greter resource utliztion 3 p<.5 vs. no reported hypoglycemi. 1. Alvrez-Guissol F, et l. Helth Qul Life Outcomes. 21;:. 2. Mrrett E, et l. BMC Res Notes. 211;4: Willims S, et l. Dibetes Res Clin Prct. 211;91: Severe Hypoglycemi Is Associted with Incresed Risk of Mortlity nd CV Events Advnce Tril Results 1 Mcrovsculr events 3.45 ( ); P<.1 Deth ny cuse 3.3 ( ); P<.1 Deth CV cuse 3.7 ( ); P<.1 Deth non-cv cuse 2. ( ); P<.1.1 VADT Results 2 Mcrovsculr events 1. ( ); P=.4 Deth ny cuse.37 ( ); P=.1 Deth CV cuse 3.73 ( ); P= Decresed Risk 1. Zoungs S, et l. ADVANCE Collbortive Group. N Engl J Med. 21;33: Duckworth W, et l. VADT Investigtors. VA Dibetes Tril (VADT) updte. ADA 7th Scientific Sessions. 21: =. 1 1 Hzrd Rtio 1 1 Incresed Risk Incretin Physiology in Combintion with GLP-1 Receptor Agonists Anne L. Leddy, MD, FACE Consulting Endocrinologist Gloucester Mthews Cre Clinic Gloucester, Virgini After food ingestion GLP-1 nd GIP is secreted from L-cells of the jejunum nd ileum Tht in turn. Secretion of GLP-1 Stimultes glucosedependent insulin secretion from -cells Suppresses glucgon secretion from -cells Slows gstric emptying Reduces food intke Degrded by DPP-4 enzyme Secretion of GIP Increses glucosedependent insulin relese Degrded by DPP-4 enzyme GLP-1 = glucgon-like peptide-1; GIP = glucose-dependent insulinotropic polypeptide. Drucker DJ. Curr Phrm Des. 21;7: Drucker DJ. Mol Endocrinol. 23 Feb;17(2): Drucker DJ, Nuck MA. Lncet. 2;3: Nuck MA. Am J Med. 29;122(Suppl 1):S3-S1. GLP-1 Receptor Agonists (GLP-1 RA) A1c reduction ~.%-2.% Multiple mechnisms of ction insulin secretion glucgon relese food intke Slows gstric emptying Advntges No hypoglycemi Weight loss some CV risk fctors (i.e., lipids, BP, hs-crp) PPG (more with short-cting gents) Disdvntges GI side effects (nuse, vomiting, dirrhe) Injection hert rte hs-crp = high sensitivity C-rective protein; BP = blood pressure; PPG = postprndil glucose. Drucker DJ, Nuck MA. Lncet. 2;3(954): Bggio LL, Drucker DJ. Gstroenterology. 27;132(): Americn Dibetes Assocition. Dibetes Cre. 215;3(suppl 1):S41-S4. Phrmcokinetic Profile of GLP-1 RAs Drug Dosing Hlf-life Durtion of Action Exentide 5-1 mcg SC twice dily 2.4 hours Short-cting Lixisentide 1-2 mcg SC dily 2-4 hours Short-cting Albiglutide 3-5 mg SC once weekly -7 dys Long-cting Dulglutide.75 mg SC once weekly 5 dys Long-cting Exentide ER 2 mg SC once weekly 2.4 hours Long-cting Lirglutide.-1. mg SC once dily 13 hours Long-cting Avilble in Europe. Not FDA pproved. ER = extended relese. Pinelli NR nd Hurren KM. The Annls of Phrmcotherpy. 211;45(7-):5-. Americn Dibetes Assocition. Dibetes Cre. 215;3(suppl 1):S41-S4. US FDA. Drugs@FDA Website. dt.fd.gov/scripts/cder/drugstfda/. EU EMA. Medicines@EMA Website.

10 Postprndil Glucose Effect of Short- nd Long-cting GLP-1 RAs: EXN vs. LIRA EXN preferentilly ffects PPG compred to Lirglutide. EXN reduced PPG significntly more fter brekfst nd dinner thn LIRA, p<.1 14 Self-Mesured Plsm Glucose (mmol/l) Before BF BF + 9 min Before Lunch Lunch + 9 min Time Before Dinner Dinner + 9 min Bedtime LIRA Bseline LIRA Week 2 EXN Bseline EXN Week 2 p<.1. PPG = postprndil glucose; BF = brekfst; EXN = exentide; LIRA = lirglutide. Buse JB, Rosenstock J, Sesti G, et l. Lncet. 29;374: PPG Effect of Short- nd Long-cting GLP-1 RAs: LIXI vs. LIRA Men Chnge from Premel Plsm Glucose (mg/dl) Lixisentide (Bseline) Lirglutide (Bseline) Mel Lixisentide (Dy 2) Lirglutide (Dy 2) p< Time fter Study Drug Administrtion GLP-1 Agonist LIXI = lixisentide; PPG = postprndil glucose. Not FDA pproved. Adpted from Kpitz C, et l. IDF 211:Poster D-74. Ptients (%) Proportion of Ptients with 2-h PPG <14 mg/dl t Dy Lixisentide Lirglutide (n=75) (n=) Why Combine GLP-1 RAs with Bsl Potentil Benefits of Combining GLP-1 RAs with Bsl GLP-1 RA No risk of hypoglycemi Associted with weight loss Minly controls PPG, more with short-cting gents Glucose dependent mechnism of ction Bsl Incresed risk of hypoglycemi Associted with weight gin Controls fsting glucose supplementtion nd individulized dosing Minimize weight gin Minimize hypoglycemi risk Tret postprndil glucose excursions Reduce or eliminte the need for prndil insulin Reduce insulin requirements PPG = postprndil glucose. Cohen ND, et l. Med J Aust. 213;199(4):24-9. Americn Dibetes Assocition. Dibetes Cre. 215;3 (suppl 1):S41-S4. Cohen ND, et l. Med J Aust. 213;199(4):24-9. Adding Prndil vs. GLP-1 RAs When Bsl Is Not Enough Bsl Bolus Add Prndil before Ech Mel Bsl Plus Add Prndil t Min Mel Bsl Add Bsl nd Titrte Bsl plus GLP-1 RAs Lifestyle Chnges plus Metformin (± other gents) Exentide BID Added to Bsl : Efficcy nd Sfety Chnge in HbA1c (%) Adults with T2DM nd HbA1c = 7.1% to 1.5% receiving glrgine ± metformin ± pioglitzone were rndomized to exentide (1 mcg twice dy) or plcebo for 3 weeks Efficcy Glrgine + PBO (n=123) Glrgine + EXN (n=13) Week Outcome PBO EXN BID only 1 reported event of mjor hypoglycemi (PBO group) p- vlue Hypoglycemi Discontinution due to Adverse 1 9 <.1 Events (% of pts) p<.1; BID = twice dily; PBO = plcebo; EXN = exentide. Buse JB, et l. Ann Intern Med. 211;154(2):

11 Glucose Level (mmol/l) Exentide BID Added to Bsl : Effect on PPG Adults with T2DM nd HbA1c = 7.1% to 1.5% receiving glrgine ± metformin ± pioglitzone were rndomized to exentide (1 mcg twice dy) or plcebo for 3 weeks SMBG Chnges Glrgine + EXN (Bseline) Glrgine + PBO (Bseline) Glrgine + EXN (3 wk) Glrgine + PBO (3 wk) Fsting Morning Middy Middy Evening Evening 3 2-hr PP Premel 2-hr PP Premel 2-hr PP Hours p<.1; p<.1; BID = twice dily; PBO = plcebo; EXN = exentide; PPG = postprndil glucose; PP = postprndil; SMBG = self monitored blood glucose. Buse JB, et l. Ann Intern Med. 211;154(2): Exentide BID Added to Bsl Effect on Dose nd Weight Dose (U/dy) Glrgine + EXN (n=13) 2 Glrgine + PBO (n=123) Chnge in Body Weight (kg) Glrgine + Plcebo Glrgine + Exentide p< Week Bseline insulin doses = 49.5 nd 47 U/dy in EXN BID nd PBO groups, respectively. Respective increses = 13 nd 2 IU/dy. EXN = exentide; PBO = plcebo. Buse JB, et l. Ann Intern Med. 211;154: Lixisentide Added to Bsl in T2DM over 24 Weeks: Efficcy Lixisentide Added to Bsl in T2DM over 24 Weeks: Weight & Hypoglycemi Chnge in HbA1c (%) A1C P<.1 LS Men Chnge (mg/dl) hour PPG P<.1 Chnge in Weight (kg) Weight Chnge -.3. Hypoglycemi (Events/pt-yr) Hypoglycemi With SU Without SU Lixisentide + + SU (n =153) Plcebo + + SU (n = 157) Not FDA pproved. PPG = postprndil glucose; SU = sulfonylure. Seino Y, et l. Dibetes Obes Metb. 212;14: Lixisentide + + SU (n =153) Plcebo + + SU (n = 157) Not FDA pproved. PPG = postprndil glucose; SU = sulfonylure. Seino Y, et l. Dibetes Obes Metb. 212;14: GLP-1 RAs Added to Bsl : Comprison with Prndil A1C (%) Added to GLAR (3 wk, N=37) EXN BID -1.1 Noninferior LIS TID -1.1 Outcome EXN BID LIS TID Weight (kg) (P<.5) Minor hypo (E/Y) Nocturnl hypo (E/Y) Nuse (%) 32 2 Added to DEG (2 wk, N=177) 2, Outcome LIRA QD ASP QD Weight (kg) (P<.5) Minor hypo (E/Y) 1..2 (P<.5) Nocturnl hypo (E/Y).2.9 (P<.5) Nuse (%) LIRA>ASP, first 2 wk Consider lowering bsl insulin dose to decrese hypoglycemi risk with GLP-1 RAs 3 degludec is not FDA pproved. DEG = insulin degludec; EPY = events per ptient-yer; EXN BID = exentide twice dily; E/Y = events per yer; GLAR = insulin glrgine; ASP = insulin sprt; LIS = insulin lispro; LIRA = lirglutide; QD = once dily; TID = three times dily. 1. Dimnt M, et l. ADA 73rd Scientific Sessions. 213;7-OR. 2. Mthieu C, et l. ADA 73rd Scientific Sessions. 213; US FDA. Drugs@FDA. A1C (%) LIRA QD -.7 P=.24 ASP QD -.4 Combining GLP-1 RAs nd Bsl GLP-1 RA Added to Bsl 1 Bsl Added to GLP-1 RA 1 Outcome EXN BID PBO DET + LIRA LIRA A1C (%) Weight (%) Minor hypoglycemi (%) b GLP-1RAs nd bsl insulin combined c improve glycemic control reltive to either clss lone, regrdless of order of ddition. 1-4 Consider lowering bsl insulin dose to decrese hypoglycemi risk with GLP-1 RAs 3 p<.5; b 1 mjor hypoglycemic event occurred in the PBO group of the GLP-1 RA dded to bsl in study; c EXN BID nd LIRA, but not EXN QW, re pproved for use with bsl, but not prndil insulin. EXN BID = exentide twice dily; DET = insulin detemir; LIRA = lirglutide; PBO = plcebo; TDD = totl dily dose. 1. Buse JB, et l. Ann Intern Med. 211;154: DeVries J, et l. Dibetes Cre. 212;35: Pwskr M, et l. Endocr Prct. 212;1: Li CJ, et l. Crdiovsc Dibetol. 212;11: US FDA. Drugs@FDA.

12 Lirglutide Added to Bsl in T2DM over 3 Weeks: Effects on A1c nd Weight A1C (%) After MET + LIRA Run-in Efficcy MET + LIRA + DET (n=12) At 3 Weeks Weight (kg) MET + LIRA (n=11) Weight Chnge After MET + LIRA Run-in At 3 Weeks MET + LIRA (OBS) (n=49) HbA1c GLP-1 RAs in Combintion with in T2DM Systemtic Review Results reported s vilble from 7 RCTs nd 15 clinicl prctice or observtionl studies including t lest 3 ptients with T2DM GLP-1 RA Added to Added to GLP-1 RA GLP-1 RA + (sequence not specified) Body Weight (kg) Dose (Units) No mjor hypoglycemi in ny group during weeks Trnsient nuse in 21% during weeks -12, 4% during weeks Bseline Endpoint 1 Bseline Endpoint 3 Bseline Endpoint Rosenstock J, et l. Dibetes. 211;(Suppl 1):A7. Abstrct 27-OR. Ech line in the grph represents study. Blen R, et l. Dibetes Obes Metb. 213;15(): Adding Rpid-Acting or GLP-1 RA to Bsl : Outcomes in Community Setting Percentge of Ptients with 1 Helthcre Visit Adding Rpid-Acting or GLP-1 RA to Bsl : Outcomes in Community Setting Men All Helthcre Costs (USD) Percentge of Ptients with 1 Helthcre Visit (%) Bsl + GLP-1 RA Bsl + Prndil p< Any Hospitliztion Dll MR, et l. Endocr Prct. 215;21:-7. p= ED Visits p= Office Visits p< Endocrinologist Visits Men All-cuse Helthcre Costs (U.S. $) 25, 2, 15, 1, 5, = $2,4 p=.2 1,413 2,21 Totl Cost = $2,51 p<.1 3,423 5,474 Inptient Cost Bsl + GLP-1 RA Bsl + Prndil = $1,2 p<.1 Outptient Cost Helth Cre Costs t 1-yer Follow-up (mtched nlysis): All-cuse nd Dibetes-relted ED = emergency deprtment. Dll MR, et l. Endocr Prct. 215;21:-7. 5,722 7,44 = $ p= ED Cost = $1,411 p<.1,747 7,33 Phrmcy Cost Bsl nd GLP-1 RA Combintion Fixed-Rtio Formultion of Glrgine/Lixisentide GLARG 2 U/LIXI 1 µg (Administered vi single pen device) Emerging Fixed Dosed Combintions of GLP-1 RAs nd Bsl Poorly controlled T2DM pts on MET (N=323) nive R Men bseline A1c.% (n=11) Glrgine (N=14) 24 week follow-up Primry outcome: A1C reduction Not FDA pproved. GLARG = insulin glrgine; LIXI = lixisentide. Rosenstock J, et l. ADA 214:Presenttion No. 241.

13 Fixed-Rtio Formultion of Glrgine/Lixisentide in T2DM over 24 Wks Fixed-Rtio Formultion of Glrgine/Lixisentide in T2DM over 24 Wks Chnge in HbA1c (%) A1C LS men difference: -.17, P=.13 LS Men Chnge (mg/dl) hour PPG LS men difference: -57, P<.1 Chnge in Weight (kg) Weight Chnge LS men difference: P<.1 No difference in hypoglycemic events between the two groups. No severe hypoglycemic events 1. GLARG 2 U/LIXI 1 µg (n =11) 2. GLARG (n = 14) Not FDA pproved; Superiority. PPG = postprndil plsm glucose; GLARG = insulin glrgine; LIXI = lixisentide. Rosenstock J, et l. ADA 214:Presenttion No GLARG 2 U/LIXI 1 µg (n =11) GLARG (n = 14) Not FDA pproved ;GLARG = insulin glrgine; LIXI = lixisentide. Rosenstock J, et l. ADA 214:Presenttion No A1C (%) Fixed-Rtio Combintion of Degludec nd Lirglutide DEG -1.3 LIRA -1.9 DEG 1 U/LIRA.3 mg 13 T2DM ptients on MET + PIO; 2 week open-lbel tril Ptients chieving A1C <7% DEG 1 U/LIRA.3 mg: 1% DEG: 5% LIRA: % DEG 1 U/LIRA.3 mg vs. DEG Weight chnge: kg; P<.1 Hypoglycemi: RR.; P<.2 DEG 1 U/LIRA.3 mg vs. LIRA Weight chnge: 2.44 kg; P<.1 Hypoglycemi: RR 7.; P<.1 Summry + metformin combintion therpy in T2DM improves glycemic control, reduces hypoglycemi, nd is typiclly considered weight-neutrl + GLP-1 RA combintion therpy in T2DM improves glycemic control, reduces hypoglycemi, nd cn induce weight loss + GLP-1 RA combintion therpy is being very ctively investigted in T1DM nd T2DM Not FDA pproved. DEG = insulin degludec; LIRA = lirglutide; MET = metformin; PIO = pioglitzone; RR = risk rtio. Gough SC, et l. Lncet Dibetes Endocrinol. 214;2(11):5-93.